title: Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease.
abstract: Chronic beryllium disease (CBD) is a granulomatous disorder characterized by an influx of beryllium (Be)-specific CD4⁺ T cells into the lung. The vast majority of these T cells recognize Be in an HLA-DP–restricted manner, and peptide is required for T cell recognition. However, the peptides that stimulate Be-specific T cells are unknown. Using positional scanning libraries and fibroblasts expressing HLA-DP2, the most prevalent HLA-DP molecule linked to disease, we identified mimotopes and endogenous self-peptides that bind to MHCII and Be, forming a complex recognized by pathogenic CD4⁺ T cells in CBD. These peptides possess aspartic and glutamic acid residues at p4 and p7, respectively, that surround the putative Be-binding site and cooperate with HLA-DP2 in Be coordination. Endogenous plexin A peptides and proteins, which share the core motif and are expressed in lung, also stimulate these TCRs. Be-loaded HLA-DP2–mimotope and HLA-DP2–plexin A4 tetramers detected high frequencies of CD4⁺ T cells specific for these ligands in all HLADP2+ CBD patients tested. Thus, our findings identify the first ligand for a CD4⁺ T cell involved in metal-induced hypersensitivity and suggest a unique role of these peptides in metal ion coordination and the generation of a common antigen specificity in CBD.
authors.affiliation: Department of Medicine, University of Colorado, Denver, Aurora, CO 80045, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Falta
authors.forename: Clemencia
authors.initials: C
authors.lastname: Pinilla
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Mack
authors.forename: Alex N
authors.initials: AN
authors.lastname: Tinega
authors.forename: Frances
authors.initials: F
authors.lastname: Crawford
authors.forename: Marc
authors.initials: M
authors.lastname: Giulianotti
authors.forename: Radleigh
authors.initials: R
authors.lastname: Santos
authors.forename: Gina M
authors.initials: GM
authors.lastname: Clayton
authors.forename: Yuxiao
authors.initials: Y
authors.lastname: Wang
authors.forename: Xuewu
authors.initials: X
authors.lastname: Zhang
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Maier
authors.forename: Philippa
authors.initials: P
authors.lastname: Marrack
authors.forename: John W
authors.initials: JW
authors.lastname: Kappler
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fontenot
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001607:Berylliosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001608:Beryllium / Q000276:immunology* / Q000378:metabolism; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D002908:Chronic Disease; D059868:HLA-DP beta-Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D059868:HLA-DP beta-Chains; C083176:HLA-DPw2 antigen; D019151:Peptide Library; D010455:Peptides; C524474:Plxna4 protein, human; D011956:Receptors, Cell Surface; D001608:Beryllium